Adverse Drug Event
Rapid-Onset Piperacillin-tazobactam Induced Thrombocytopenia
Journal of Pharmacy Practice 1-3 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190014566302 jpp.sagepub.com
Shamsuddin Shaik, MD1, Haseeb A. Kazi, MD2, and Peter T. Ender, MD3
Abstract Thrombocytopenia can occur from a variety of etiologies. Drug-induced thrombocytopenia is known to occur with beta-lactam medications, but often in the setting of prolonged use. We describe 2 patients who developed rapid-onset thrombocytopenia from piperacillin/tazobactam. Other causes of immediate thrombocytopenia were excluded. These cases describe a rare presentation of rapid-onset thrombocytopenia in a commonly used medication. Keywords internal medicine, drug information
Introduction Thrombocytopenia is defined as a platelet count of less than 150 thousand/mL and can occur from underproduction, peripheral destruction, or splenic sequestration of platelets. These categories include a variety of etiologies, including infection, malignancy, alcohol abuse, primary hematologic processes, disseminated intravascular coagulation (DIC), and medications.1 Drug-induced thrombocytopenia is known to occur with beta-lactam medications, but often with prolonged use. Thrombocytopenia is a rare side effect of piperacillin/tazobactam, most often reported to occur after several days of use.2-10 Although no clear definition of immediate onset of thrombocytopenia exists, we describe 2 patients who developed rapid-onset thrombocytopenia from piperacillin/tazobactam. Other causes of immediate thrombocytopenia were ruled out, and the platelet count recovered after discontinuation of the antimicrobial in both cases. These cases highlight rapid-onset thrombocytopenia with this commonly used medication.
Case Presentation Case 1 A 47-year-old Hispanic female with chronic lung disease, hypertension, a rectal mass, and HIV was admitted with 1 week of fever, chills, and productive cough without hemoptysis. She had multiple prior admissions for resistant pseudomonal and pneumococcal pneumonia with sepsis, including ventilatordependent respiratory failure. She was on abacavir 600 mg orally daily, atazanavir 300 mg orally daily, lamivudine 300 mg orally daily, and ritonavir 100 mg orally daily for the last 6 months with a recent CD4 >200/mL and a viral load of 30 copies/mL. Her other medications during this hospitalization included albuterol 2 puffs inhaled as needed (PRN), metoprolol
25 mg orally every 8 hours, tiotropium 18 mg daily, tramadol 50 mg orally every 6 hours, sulfamethoxazole/trimethoprim 400-80 mg 2 tablets orally twice daily, zolpidem 10 mg orally nightly PRN, and benzonatate 200 mg orally 3 times daily. The patient had an allergy to oxycodone/acetaminophen and was not taking any herbal or over-the-counter medications. There was no history of alcohol, tobacco, or drug use. On admission, the hemoglobin was 11.2 g/dL, white blood cells (WBCs) 17.76 thousand/mL, and platelets 198 thousand/ mL. Initially, she received 1 dose of ceftriaxone 1 g intravenously (IV) and azithromycin 500 mg IV. On day 2, piperacillin/tazobactam 4.5 g IV every 6 hours was started for health care-associated pneumonia (HCAP) to cover for Pseudomonas aeruginosa. After 2 doses of piperacillin/tazobactam, which was 11 hours from the first administered dose, the platelet count fell to 7.0 thousand/mL. Piperacillin/tazobactam was discontinued along with sulfamethoxazole/trimethoprim and replaced with aztreonam 1 g every 8 hours. The platelet count gradually increased to 133 thousand/mL 5 days later without any other intervention (Table 1). No heparin was ever administered and there was no evidence of spontaneous bleeding. Five months later she was readmitted for HCAP with an initial platelet count of 157 thousand/mL. Her home medications were the same as the previous admission except she was no 1 Department of Internal Medicine, St Luke’s University Hospital, Bethlehem, PA, USA 2 Department of Medicine, Emory University Hospital, Atlanta, GA, USA 3 Section of Infectious Diseases, St Luke’s University Hospital, Bethlehem, PA, USA
Corresponding Author: Haseeb A. Kazi, Department of Medicine, Emory University Hospital, 1364 Clifton Rd NE, Box M7, Atlanta, GA 30322, USA. Email: [email protected]
2
Journal of Pharmacy Practice
Table 1. Summary of Piperacillin/Tazobactam Administration. Admission platelet count Patient 1—first hospitalization Patient 1—second hospitalization Patient 2
Hours after piperacilline/ tazobactam started
Platelet count after administration
Platelet count after discontinuation 133 thousand/mL (5 days after discontinuation) 183 thousand/mL (6 days after discontinuation) 118 thousand/mL (24 days after discontinuation)
198 thousand/mL
11
7 thousand/mL
157 thousand/mL
19
40 thousand/mL
325 thousand/mL
14
3 thousand/mL
longer taking sulfamethoxazole/trimethoprim. There was no over-the-counter or herbal medication use. She was inadvertently given a single dose of 3.375 mg of piperacillin/tazobactam. No other antibiotics were given prior to the piperacillin/ tazobactam administration. The patient had no hemodynamic instability or respiratory deterioration to suggest progressive sepsis or anaphylaxis. The platelet count fell to 40 thousand/ mL after 19 hours from time of administration. The patient was given no additional doses of piperacillin/tazobactam and her platelet count gradually improved to 183 thousand/mL 6 days later (Table 1). The patient received meropenem 1 g IV every 8 hours to complete treatment of her HCAP. Once again, no heparin was administered during this admission.
Case 2 A 55-year-old female with a history of hearing loss, degenerative joint disease, urinary incontinence, and asthma was admitted for elective resection of rectal carcinoma. Computed tomography of the abdomen and pelvis done for a postoperative fever revealed a large fluid collection that was subsequently drained percutaneously. Cefazolin 1 g with metronidazole 500 mg was given for 2 doses, then switched to ampicillin/sulbactam 3 g IV every 6 hours for 3 doses. Other medications were pantoprazole 40 mg IV daily, heparin 5000 units subcutaneously every 8 hours, diphenhydramine 25 mg IV every 6 hours PRN, ondansetron 4 mg IV every 4 hours PRN, ketorolac 30 mg IV every 6 hours PRN, and oxycodone-acetaminophen 5-325 mg orally every 4 hours PRN. She did not use alcohol, tobacco, or recreational drugs. There were no drug allergies, and she was not taking any over-the-counter or herbal medications. Laboratory studies revealed a hemoglobin of 8.0 g/dL, WBC of 5.74 thousand/mL, and platelets of 325 thousand/mL. To expand the antimicrobial spectrum for this infection, ampicillin/sulbactam was discontinued and piperacillin/tazobactam 4.5 g IV every 6 hours was started. After 3 doses, the platelet count fell to 3.0 thousand/mL, which was 14 hours after administration of the first dose of piperacillin/tazobactam. Antimicrobial treatment was changed to levofloxacin 500 mg IV daily and metronidazole 500 mg IV every 8 hours. Heparin-induced thrombocytopenia (HIT) enzyme-linked immunosorbent assay and DIC panel were negative. The platelet count gradually recovered to 118 thousand/mL 24 days after
discontinuation of piperacillin-tazobactam without any other intervention (Table 1). There was no spontaneous bleeding or thrombosis while the patient was thrombocytopenic. Given the significant thrombocytopenia, the patient was not rechallenged with piperacillin/tazobactam and eventually discharged home on oral levofloxacin and metronidazole.
Discussion Thrombocytopenia is a serious but uncommon adverse effect of piperacillin/tazobactam. Previously reported cases of thrombocytopenia have been of gradual onset, occurring days after receiving the antimicrobial, ranging from 4 days to over 3 weeks after administration of piperacillin/tazobactam.2-10 The cases varied in their type of infection, underlying comorbidities, medications, demographics, and level of care within the hospital. Other medications that could also cause thrombocytopenia were given in some of the described patients. Several mechanisms of action have been proposed as the cause of beta-lactam–induced thrombocytopenia. Some reports suggest thrombocytopenia is associated with the presence of antibodies that attach to platelet surfaces in the presence of piperacillin.4,9,10 More specifically, piperacillin/tazobactam may induce a reversible conformation in the platelet membrane generating a neoantigen. This neoantigen may lead to the synthesis of antibodies to the drug-platelet membrane complex, which can ultimately cause antibody-mediated platelet destruction.4,11,12 One recent case report described thrombocytopenia after 1 dose of piperacillin/tazobactam with improvement in the platelet count after discontinuation of the antibiotic.13 Flow cytometry performed 1 month later showed immunoglobulin G antibodies against piperacillin. While discontinuation of the offending agent is the initial treatment of drug-induced thrombocytopenia, hemodialysis and intravenous immunoglobulin have been used in refractory cases.5,7,8 In both of the described patients, immediate thrombocytopenia occurred after piperacillin/tazobactam exposure. The cause was confirmed with rechallenge and platelet recovery with discontinuation in the first case. HIT testing was not done as the patient did not receive any heparin products. Spontaneous bleeding never occurred with these episodes of severe thrombocytopenia. Based on the Naranjo Adverse Drug Reaction Probability Scale, the rapid-onset thrombocytopenia from
Shaik et al piperacillin/tazobactam in this case can be classified as ‘‘probable.’’ The case can also be classified as ‘‘definite’’ with level I evidence based on the Criteria for Assessing Reports of DrugInduced Thrombocytopenia and Levels of Evidence for a Causal Relation between the Drug and Thrombocytopenia.14,15 In the second case, no other clear cause of thrombocytopenia was found and recovery of the platelet counts occurred after discontinuation. One could argue that the prior 3 doses of ampicillin/sulbactam and 2 doses of cefazolin may have played a role in the development of thrombocytopenia. These other medications could cause thrombocytopenia, but the timing of administration of the piperacillin/tazobactam seems to correlate strongly with the development of thrombocytopenia as does the resolution of the thrombocytopenia with discontinuation of the piperacillin/ tazobactam. Using the Naranjo Adverse Drug Reaction Probability Scale, this case is classified as a ‘‘probable’’ piperacillin/tazobactam-induced thrombocytopenia. This case can also be classified as ‘‘probable’’ with level II evidence based on the Criteria for Assessing Reports of Drug-Induced Thrombocytopenia and Levels of Evidence for a Causal Relation between the Drug and Thrombocytopenia.14,15 Other conditions that could have contributed to the thrombocytopenia in our patients are HIV and sepsis.1 However, despite the history of HIV, the patient had a normal platelet count on admission. In addition, trimethoprim, which can cause thrombocytopenia, was discontinued in the first hospitalization and never used during the second hospitalization.16 Sepsis syndrome, which was present in both cases, can cause acute thrombocytopenia from increased platelet consumption or decreased platelet production.1 However, the initial normal platelet count with the sepsis syndrome and the platelet recovery after discontinuation of the piperacillin/tazobactam argue against this possibility. No true or exact definition of rapid- or late-onset thrombocytopenia exists, but in our patients we observed the onset in less than 24 hours. One study focusing on antibiotics and thrombocytopenia demonstrated piperacillin/tazobactaminduced thrombocytopenia in critically ill patients within 24 hours.17 The study did not include details surrounding the development of thrombocytopenia. They also included mild to moderate thrombocytopenia as they defined thrombocytopenia as absolute (
Rapid-Onset Piperacillin-tazobactam Induced Thrombocytopenia
Journal of Pharmacy Practice 1-3 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190014566302 jpp.sagepub.com
Shamsuddin Shaik, MD1, Haseeb A. Kazi, MD2, and Peter T. Ender, MD3
Abstract Thrombocytopenia can occur from a variety of etiologies. Drug-induced thrombocytopenia is known to occur with beta-lactam medications, but often in the setting of prolonged use. We describe 2 patients who developed rapid-onset thrombocytopenia from piperacillin/tazobactam. Other causes of immediate thrombocytopenia were excluded. These cases describe a rare presentation of rapid-onset thrombocytopenia in a commonly used medication. Keywords internal medicine, drug information
Introduction Thrombocytopenia is defined as a platelet count of less than 150 thousand/mL and can occur from underproduction, peripheral destruction, or splenic sequestration of platelets. These categories include a variety of etiologies, including infection, malignancy, alcohol abuse, primary hematologic processes, disseminated intravascular coagulation (DIC), and medications.1 Drug-induced thrombocytopenia is known to occur with beta-lactam medications, but often with prolonged use. Thrombocytopenia is a rare side effect of piperacillin/tazobactam, most often reported to occur after several days of use.2-10 Although no clear definition of immediate onset of thrombocytopenia exists, we describe 2 patients who developed rapid-onset thrombocytopenia from piperacillin/tazobactam. Other causes of immediate thrombocytopenia were ruled out, and the platelet count recovered after discontinuation of the antimicrobial in both cases. These cases highlight rapid-onset thrombocytopenia with this commonly used medication.
Case Presentation Case 1 A 47-year-old Hispanic female with chronic lung disease, hypertension, a rectal mass, and HIV was admitted with 1 week of fever, chills, and productive cough without hemoptysis. She had multiple prior admissions for resistant pseudomonal and pneumococcal pneumonia with sepsis, including ventilatordependent respiratory failure. She was on abacavir 600 mg orally daily, atazanavir 300 mg orally daily, lamivudine 300 mg orally daily, and ritonavir 100 mg orally daily for the last 6 months with a recent CD4 >200/mL and a viral load of 30 copies/mL. Her other medications during this hospitalization included albuterol 2 puffs inhaled as needed (PRN), metoprolol
25 mg orally every 8 hours, tiotropium 18 mg daily, tramadol 50 mg orally every 6 hours, sulfamethoxazole/trimethoprim 400-80 mg 2 tablets orally twice daily, zolpidem 10 mg orally nightly PRN, and benzonatate 200 mg orally 3 times daily. The patient had an allergy to oxycodone/acetaminophen and was not taking any herbal or over-the-counter medications. There was no history of alcohol, tobacco, or drug use. On admission, the hemoglobin was 11.2 g/dL, white blood cells (WBCs) 17.76 thousand/mL, and platelets 198 thousand/ mL. Initially, she received 1 dose of ceftriaxone 1 g intravenously (IV) and azithromycin 500 mg IV. On day 2, piperacillin/tazobactam 4.5 g IV every 6 hours was started for health care-associated pneumonia (HCAP) to cover for Pseudomonas aeruginosa. After 2 doses of piperacillin/tazobactam, which was 11 hours from the first administered dose, the platelet count fell to 7.0 thousand/mL. Piperacillin/tazobactam was discontinued along with sulfamethoxazole/trimethoprim and replaced with aztreonam 1 g every 8 hours. The platelet count gradually increased to 133 thousand/mL 5 days later without any other intervention (Table 1). No heparin was ever administered and there was no evidence of spontaneous bleeding. Five months later she was readmitted for HCAP with an initial platelet count of 157 thousand/mL. Her home medications were the same as the previous admission except she was no 1 Department of Internal Medicine, St Luke’s University Hospital, Bethlehem, PA, USA 2 Department of Medicine, Emory University Hospital, Atlanta, GA, USA 3 Section of Infectious Diseases, St Luke’s University Hospital, Bethlehem, PA, USA
Corresponding Author: Haseeb A. Kazi, Department of Medicine, Emory University Hospital, 1364 Clifton Rd NE, Box M7, Atlanta, GA 30322, USA. Email: [email protected]
2
Journal of Pharmacy Practice
Table 1. Summary of Piperacillin/Tazobactam Administration. Admission platelet count Patient 1—first hospitalization Patient 1—second hospitalization Patient 2
Hours after piperacilline/ tazobactam started
Platelet count after administration
Platelet count after discontinuation 133 thousand/mL (5 days after discontinuation) 183 thousand/mL (6 days after discontinuation) 118 thousand/mL (24 days after discontinuation)
198 thousand/mL
11
7 thousand/mL
157 thousand/mL
19
40 thousand/mL
325 thousand/mL
14
3 thousand/mL
longer taking sulfamethoxazole/trimethoprim. There was no over-the-counter or herbal medication use. She was inadvertently given a single dose of 3.375 mg of piperacillin/tazobactam. No other antibiotics were given prior to the piperacillin/ tazobactam administration. The patient had no hemodynamic instability or respiratory deterioration to suggest progressive sepsis or anaphylaxis. The platelet count fell to 40 thousand/ mL after 19 hours from time of administration. The patient was given no additional doses of piperacillin/tazobactam and her platelet count gradually improved to 183 thousand/mL 6 days later (Table 1). The patient received meropenem 1 g IV every 8 hours to complete treatment of her HCAP. Once again, no heparin was administered during this admission.
Case 2 A 55-year-old female with a history of hearing loss, degenerative joint disease, urinary incontinence, and asthma was admitted for elective resection of rectal carcinoma. Computed tomography of the abdomen and pelvis done for a postoperative fever revealed a large fluid collection that was subsequently drained percutaneously. Cefazolin 1 g with metronidazole 500 mg was given for 2 doses, then switched to ampicillin/sulbactam 3 g IV every 6 hours for 3 doses. Other medications were pantoprazole 40 mg IV daily, heparin 5000 units subcutaneously every 8 hours, diphenhydramine 25 mg IV every 6 hours PRN, ondansetron 4 mg IV every 4 hours PRN, ketorolac 30 mg IV every 6 hours PRN, and oxycodone-acetaminophen 5-325 mg orally every 4 hours PRN. She did not use alcohol, tobacco, or recreational drugs. There were no drug allergies, and she was not taking any over-the-counter or herbal medications. Laboratory studies revealed a hemoglobin of 8.0 g/dL, WBC of 5.74 thousand/mL, and platelets of 325 thousand/mL. To expand the antimicrobial spectrum for this infection, ampicillin/sulbactam was discontinued and piperacillin/tazobactam 4.5 g IV every 6 hours was started. After 3 doses, the platelet count fell to 3.0 thousand/mL, which was 14 hours after administration of the first dose of piperacillin/tazobactam. Antimicrobial treatment was changed to levofloxacin 500 mg IV daily and metronidazole 500 mg IV every 8 hours. Heparin-induced thrombocytopenia (HIT) enzyme-linked immunosorbent assay and DIC panel were negative. The platelet count gradually recovered to 118 thousand/mL 24 days after
discontinuation of piperacillin-tazobactam without any other intervention (Table 1). There was no spontaneous bleeding or thrombosis while the patient was thrombocytopenic. Given the significant thrombocytopenia, the patient was not rechallenged with piperacillin/tazobactam and eventually discharged home on oral levofloxacin and metronidazole.
Discussion Thrombocytopenia is a serious but uncommon adverse effect of piperacillin/tazobactam. Previously reported cases of thrombocytopenia have been of gradual onset, occurring days after receiving the antimicrobial, ranging from 4 days to over 3 weeks after administration of piperacillin/tazobactam.2-10 The cases varied in their type of infection, underlying comorbidities, medications, demographics, and level of care within the hospital. Other medications that could also cause thrombocytopenia were given in some of the described patients. Several mechanisms of action have been proposed as the cause of beta-lactam–induced thrombocytopenia. Some reports suggest thrombocytopenia is associated with the presence of antibodies that attach to platelet surfaces in the presence of piperacillin.4,9,10 More specifically, piperacillin/tazobactam may induce a reversible conformation in the platelet membrane generating a neoantigen. This neoantigen may lead to the synthesis of antibodies to the drug-platelet membrane complex, which can ultimately cause antibody-mediated platelet destruction.4,11,12 One recent case report described thrombocytopenia after 1 dose of piperacillin/tazobactam with improvement in the platelet count after discontinuation of the antibiotic.13 Flow cytometry performed 1 month later showed immunoglobulin G antibodies against piperacillin. While discontinuation of the offending agent is the initial treatment of drug-induced thrombocytopenia, hemodialysis and intravenous immunoglobulin have been used in refractory cases.5,7,8 In both of the described patients, immediate thrombocytopenia occurred after piperacillin/tazobactam exposure. The cause was confirmed with rechallenge and platelet recovery with discontinuation in the first case. HIT testing was not done as the patient did not receive any heparin products. Spontaneous bleeding never occurred with these episodes of severe thrombocytopenia. Based on the Naranjo Adverse Drug Reaction Probability Scale, the rapid-onset thrombocytopenia from
Shaik et al piperacillin/tazobactam in this case can be classified as ‘‘probable.’’ The case can also be classified as ‘‘definite’’ with level I evidence based on the Criteria for Assessing Reports of DrugInduced Thrombocytopenia and Levels of Evidence for a Causal Relation between the Drug and Thrombocytopenia.14,15 In the second case, no other clear cause of thrombocytopenia was found and recovery of the platelet counts occurred after discontinuation. One could argue that the prior 3 doses of ampicillin/sulbactam and 2 doses of cefazolin may have played a role in the development of thrombocytopenia. These other medications could cause thrombocytopenia, but the timing of administration of the piperacillin/tazobactam seems to correlate strongly with the development of thrombocytopenia as does the resolution of the thrombocytopenia with discontinuation of the piperacillin/ tazobactam. Using the Naranjo Adverse Drug Reaction Probability Scale, this case is classified as a ‘‘probable’’ piperacillin/tazobactam-induced thrombocytopenia. This case can also be classified as ‘‘probable’’ with level II evidence based on the Criteria for Assessing Reports of Drug-Induced Thrombocytopenia and Levels of Evidence for a Causal Relation between the Drug and Thrombocytopenia.14,15 Other conditions that could have contributed to the thrombocytopenia in our patients are HIV and sepsis.1 However, despite the history of HIV, the patient had a normal platelet count on admission. In addition, trimethoprim, which can cause thrombocytopenia, was discontinued in the first hospitalization and never used during the second hospitalization.16 Sepsis syndrome, which was present in both cases, can cause acute thrombocytopenia from increased platelet consumption or decreased platelet production.1 However, the initial normal platelet count with the sepsis syndrome and the platelet recovery after discontinuation of the piperacillin/tazobactam argue against this possibility. No true or exact definition of rapid- or late-onset thrombocytopenia exists, but in our patients we observed the onset in less than 24 hours. One study focusing on antibiotics and thrombocytopenia demonstrated piperacillin/tazobactaminduced thrombocytopenia in critically ill patients within 24 hours.17 The study did not include details surrounding the development of thrombocytopenia. They also included mild to moderate thrombocytopenia as they defined thrombocytopenia as absolute (
